The Level of Hepatitis B Virus Replication Is Not Affected by Protein ISG15 Modification but Is Reduced by Inhibition of UBP43 (USP18) Expression

Kim, Junghwan; Luo, Jiann-Kae; Zhang, Dong‐Er

doi:10.4049/jimmunol.181.9.6467

Cited by 69 publications

(59 citation statements)

References 45 publications

(51 reference statements)

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“…For example, ISG15 can have an antiviral effect on Sindbis virus, influenza virus, HSV, human immunodeficiency virus (HIV) and Ebola virus (Lenschow et al, 2005(Lenschow et al, , 2007Okumura et al, 2006;Zhang et al, 2007), but ISGylation does not contribute to murine susceptibility to lymphocytic choriomeningitis virus and vesicular stomatitis virus , nor to hepatitis B virus replication in ISGylation-deficient mice (Ube1L 2/2 ) (Kim et al, 2008a). Although ISG15 may also promote viral production by acting as a negative regulator of the innate immune response through its conjugation to RIG-I (Kim et al, 2008b), this mechanism is unlikely to contribute to our observed effects, as Huh7.5 cells are deficient in RIG-I (Sumpter et al, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…ISG15 2/2 mice are more susceptible to influenza A and B viruses, herpes simplex virus type 1 (HSV-1), Sindbis virus and murine gammaherpesvirus 68 infection; for Sindbis virus, this effect is dependent on ISGylation (Lenschow et al, 2007). Whilst these studies suggest a general role for ISG15 as an antiviral agent, a recent report found that ISG15 can inhibit IFN responses after infection by Newcastle disease virus (Kim et al, 2008a). ISGylation of the antiviral RIG-I enzyme inhibited IFN signalling in MEF cells (Kim et al, 2008b).…”

Section: Introductionmentioning

confidence: 99%

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ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

Chen

Sun

Meng

et al. 2009

Journal of General Virology

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Upregulation of interferon (IFN)-stimulated genes (ISGs), including IFN-stimulated gene 15 (ISG15) and other members of the ISG15 pathway, in pre-treatment liver tissue of patients chronically infected with hepatitis C virus (HCV) is associated with subsequent treatment failure (pegylated IFN-a/ribavirin). This study assessed the effect of ISG15 on HCV production in vitro. The levels of ISG15 and of its conjugation to target proteins (ISGylation) were increased by plasmid transfection, but ISGylation was inhibited by small interfering RNA directed against the E1 activating enzyme, Ube1L, in Huh7.5 cells. Cells were infected with HCV FL-J6/JFH virus, and HCV RNA and viral titres were determined. Levels of both HCV RNA and virus increased when levels of ISG15 and ISGylation were increased, and decreased when ISGylation was inhibited. The effects of ISGylation on HCV were independent of upstream IFN signalling: IFN-a-induced ISG expression was not altered by Ube1L knockdown. Thus, although ISG15 has antiviral activity against most viruses, ISG15 promotes HCV production. HCV might exploit ISG15 as a host immune evasion mechanism, and this may in part explain how increased expression of ISGs, especially ISG15, correlates with subsequent IFN-based treatment failure. INTRODUCTIONHepatitis C virus (HCV) is adept at evading host antiviral mechanisms and is often resistant to the current standard of care -combination treatment with pegylated interferon (IFN)-a and ribavirin (PegIFN/Rib). This regimen eradicates the virus in only 50 % of cases. A number of mechanisms contribute to evasion and treatment resistance, including cleavage of the RIG-I adaptor protein IPS1/ MAVS/Cardif by the HCV NS3/NS4A protease and modulation of the host response by the HCV core protein Loo et al., 2006). However, none of these mechanisms has consistently been demonstrated to play a role in the clinical disease and thus cannot explain the ability of the virus to escape the host response in patients.Response to treatment can be predicted by levels of expression of IFN-stimulated genes (ISGs) in the liver prior to initiation of PegIFN/Rib treatment. Non-responders have increased expression of a number of ISGs (Chen et al., 2005;Feld et al., 2007; Asahina et al., 2008;Asselah et al., 2008;Sarasin-Filipowicz, et al., 2008). Three of these ISGs are components of the ISG15 ubiquitin-like pathway. ISG15 was the first ubiquitin-like protein to be described and, like its homologue ubiquitin, is conjugated to proteins in a tightly regulated process called ISGylation. The ISG15 E1 activating protein, Ube1L, coordinates with the E2 conjugating enzyme (UbcH8) and the E3 ligase (CEB1) to join the C terminus of ISG15 to a wide variety of proteins (Loeb & Haas, 1992). ISG15 can be removed from its target proteins by USP18, an ISG15 protease (Kim et al., 2008b). Thus, ISG15 inhibits virus production for many viruses, but may promote production of some.In this study, we examined the role of ISG15 and ISGylation in HCV production in vitro, using the FL-J6/JFH...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

Chen

Sun

Meng

et al. 2009

Journal of General Virology

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“…UBP43-deficient mice show a severe phenotype characterized by brain cell injury, poly(I-C) hypersensitivity, and premature death (36,46). Interestingly, they are resistant to otherwise fatal cerebral infections with lymphocytic choriomeningitis virus and vesicular stomatitis virus (45) and have substantially lower hepatitis B virus DNA levels in a mouse model of acute hepatitis B (22). Importantly, USP18/UBP43 is elevated in livers of future nonresponders to pegIFN-␣ therapy (5,47).…”

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confidence: 99%

Alpha Interferon Induces Long-Lasting Refractoriness of JAK-STAT Signaling in the Mouse Liver through Induction of USP18/UBP43

Sinnreich

Wang

Yan

et al. 2009

Molecular and Cellular Biology

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161

145

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Recombinant alpha interferon (IFN-␣) is used for the treatment of viral hepatitis and some forms of cancer. During these therapies IFN-␣ is injected once daily or every second day for several months. Recently, the long-acting pegylated IFN-␣ (pegIFN-␣) has replaced standard IFN-␣ in therapies of chronic hepatitis C because it is more effective, supposedly by inducing a long-lasting activation of IFN signaling pathways. IFN signaling in cultured cells, however, becomes refractory within hours, and little is known about the pharmacodynamic effects of continuously high IFN-␣ serum concentrations. To investigate the behavior of the IFN system in vivo, we repeatedly injected mice with IFN-␣ and analyzed its effects in the liver. Within hours after the first injection, IFN-␣ signaling became refractory to further stimulation. The negative regulator SOCS1 was rapidly upregulated and likely responsible for early termination of IFN-␣ signaling. For long-lasting refractoriness, neither SOCS1 nor SOCS3 were instrumental. Instead, we identified the inhibitor USP18/ UBP43 as the key mediator. Our results indicate that the current therapeutic practice using long-lasting pegIFN-␣ is not well adapted to the intrinsic properties of the IFN system. Targeting USP18 expression may allow to exploit the full therapeutic potential of recombinant IFN-␣.

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“…For example, it has been shown that a reduced level of expression of USP18/UBP43 results in increased AV activity against Sindbis virus, hepatitis B (HepB) virus, and vesicular stomatitis virus (VSV) in knockout mice (17,20,24,25,31). USP18/ UBP43 can also negatively regulate IFN signaling by binding to IFNAR2 and downregulating the JAK-STAT pathway (24); this property is distinct from its ISG15 deconjugation activity described above.…”

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confidence: 99%

Knockdown of USP18 Increases Alpha 2a Interferon Signaling and Induction of Interferon-Stimulating Genes but Does Not Increase Antiviral Activity in Huh7 Cells

Murray¹,

Burden²,

Horscroft³

et al. 2011

Antimicrob Agents Chemother

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The current standard of care for hepatitis C virus (HCV) patients is cotreatment with human alpha interferon (IFN-␣) and ribavirin. The host factor USP18 functions to regulate the interferon signaling pathway by acting as an off-switch. In order to understand whether the inhibition of USP18 represents a valid target for the enhancement of interferon treatment for chronic viral diseases, we have used a wide range of RNA interference (RNAi) reagents to suppress USP18 gene expression in Huh7 cell lines. We demonstrate that a USP18 knockdown results in IFN-␣2a signaling (measured by increased IFN-stimulated response element [ISRE] reporter gene activity, 2,5-oligoadenylate synthetase [2-5 OAS] expression, and ISG15 induction) that is increased by ϳ100-fold, whereas the antiviral (AV) potency in both the Huh7 HCV subgenomic replicon assay and the Huh7.5 HCV infectious virus assay increased by ϳ3-fold. While the degree of the USP18 knockdown of USP18 elicited by the different RNAi reagents correlated with the enhancement of IFN-␣2a signaling, it did not correlate with the enhancement of AV activity. The failure of increased IFN-␣2a signaling to fully translate into increased AV potency was also observed for encephalomyocarditis virus (EMCV) assays using Huh7.5 cells. These data suggest that the IFN-mediated AV response in Huh7.5 cells has only a limited dependence on USP18 activity.Hepatitis C virus (HCV) infection is a major cause of liver disease, with more than 170 million infected people worldwide at risk of liver failure and hepatocarcinoma (19). The current standard of care (SOC), using pegylated alpha 2a interferon (IFN-␣2a) and ribavirin, is failing 40 to 50% of treated HCV patients, so new therapies are urgently required (18). Novel investigational directly acting antivirals (DAAs) targeting HCV protease (e.g., telaprevir and boceprevir) and polymerase (e.g., RG7128 and filibuvir) are progressing through clinical trials. However, these reagents will initially be added to the current SOC, and drug-resistant mutations will likely be selected in patients whose virus is not fully suppressed (8). One strategy for reducing the probability of the emergence of resistant virus would be to target host functions, because these genetic loci are not under the control of the promiscuous HCV replication machinery and therefore could increase the barrier to developing drug resistance.IFN-␣2a plays a crucial role in innate immunity against viral infections such as HCV (29). After binding to a specific receptor complex (composed of IFNAR1 and IFNAR2), signaling is initiated through the phosphorylation of STAT-1 and STAT-2 by JAK and Tyk2 kinases, and the subsequent heterodimerization of the phosphorylated STATs leads to an association with interferon regulatory factor 9 (IRF-9) to form IFN-stimulated gene (ISG) factor 3 (ISGF-3). This complex can bind to IFNstimulated response elements (ISREs) found in the promoter regions of many ISGs. As a result, around 300 ISGs are transcriptionally upregulated, including canonical antivir...

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The Level of Hepatitis B Virus Replication Is Not Affected by Protein ISG15 Modification but Is Reduced by Inhibition of UBP43 (USP18) Expression

Cited by 69 publications

References 45 publications

ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

ISG15, a ubiquitin-like interferon-stimulated gene, promotes hepatitis C virus production in vitro: implications for chronic infection and response to treatment

Alpha Interferon Induces Long-Lasting Refractoriness of JAK-STAT Signaling in the Mouse Liver through Induction of USP18/UBP43

Knockdown of USP18 Increases Alpha 2a Interferon Signaling and Induction of Interferon-Stimulating Genes but Does Not Increase Antiviral Activity in Huh7 Cells

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